This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project is applying powerful proteomics technologies to investigate changes resulting from the pathologic events associated with concomitant lentiviral infection and substance abuse. Opioids and HIV proteins act synergistically to destabilize immune function by affecting monocytes and lymphocytes;this has been proposed as a mechanism underlying the increased frequency and severity of HIV encephalitis among HIV-positive, heroin-abusing individuals. Opioids may also exacerbate simian immunodeficiency virus (SIV) infections, as morphine-dependent rhesus macaques exhibit increased virus replication, exacerbated disease, and accelerated death when challenged with SIVmac239. The central research questions we wish to address are: 1) do opioids suppress protective immune responses and foster disease progression? Or 2) do opioids suppress inflammatory responses that would otherwise accelerate disease progression and, in so doing, slow the pace of disease? The complex interactions between opioids and immunodeficiency viruses are being studied in a well-defined nonhuman primate model of lentiviral pathogenesis induced by SIV and in HIV-infected and uninfected human subjects, treated or not with exogenous opioids. We aim to identify the quantitative proteomic biosignatures and profiles that define and predict the impact of opioids on lentiviral disease progression, with particular emphasis on the neurological sequelae that accompany AIDS. Specimens from nonhuman primates have been obtained over the course of a 3-month protocol, both in the presence or absence of morphine, as well as in the presence or absence of SIVagm.sab challenge;infection with SIVagm.sab was done in pigtailed macaques and African green monkeys, which normally exhibit pathogenic and non-pathogenic infections, respectively. Our efforts to explore the effect of opioids on proteomic, immunologic, and genomic profiles will benefit from the extensive experience of the investigators, existing sample sets, comparison of human and nonhuman primate responses, and the extensive use of complementary data and techniques (e.g., immunologic and microarray assays).